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Transketolase-like 1 potentiates PD-1 blockade in hepatocellular carcinoma by glycolysis to prime dendritic cell lactylation

Signal Transduct Target Ther. 2026 Sep 28;11(1):418. doi: 10.1038/s41392-026-02875-2.

ABSTRACT

Hepatocellular carcinoma (HCC) exhibits a suboptimal response to immune checkpoint blockade (ICB) therapy; to overcome this resistance, we aimed to delineate key immune resistance factors via multi-omics analysis, develop strategies to block their immunosuppressive axes, and engineer a targeted nanosystem to enhance immunotherapy efficacy against PD-1 resistance in HCC. Using transcriptomic and proteomic data from anti-PD-1-treated HCC patients, along with functional validation in murine models and mechanistic molecular and cell biology studies, we identified transketolase-like 1 (TKTL1) as a dual-nature biomarker where overexpression predicted poor baseline prognosis yet enhanced response to ICB. Mechanistically, TKTL1 diverts glucose flux into glycolysis rather than pentose phosphate pathway (PPP), recruiting USP9X to deubiquitinate and stabilize HIF-1α, which upregulates HK2 to amplify glycolytic output and lactate accumulation. This metabolic rewiring orchestrates dual immunosuppressive circuits through HIF-1α-driven CCL4 secretion recruiting PD-L1high dendritic cells (DCs), coupled with lactate-induced TRIM28K408 lactylation that stabilizes PD-L1 by blocking ubiquitin-mediated degradation. We engineered a hepatoma-membrane-coated MnO₂ nanosystem (CQLH) co-delivering a TKTL1 inhibitor and lactate oxidase, which disrupted the TKTL1-HIF-1α-HK2 axis, depleted lactate, and reprogrammed the tumor microenvironment, thereby enhanced anti-PD-1 therapy to suppress tumor growth, especially in TKTL1high tumors. These findings define a critical "TKTL1-glycolysis-lactate-DC" axis driving anti-PD-1 sensitivity in HCC, position TKTL1 as both a potential biomarker for ICB response and a tractable therapeutic target, and demonstrate that the targeted CQLH nanosystem overcomes resistance and enhances anti-PD-1 efficacy, offering a precision immunotherapeutic strategy for TKTL1high HCC.

PMID:42802226 | PMC:PMC13616917 | DOI:10.1038/s41392-026-02875-2

Occamy-1.0: Open Pareto-frontier 35B Intelligence for Co-work

arXiv:2609.11977v1 Announce Type: new Abstract: Co-work agents execute complex workflows that combine information gathering, tool use, coding, and file manipulation across many model invocations. Because cost and latency accumulate over the full episode, their practical value depends not only on peak capability but also on how efficiently that capability is delivered. Yet many steps in everyday work emphasize state tracking, coordination, recovery, and follow-through rather than frontier-scale reasoning. We present Occamy-1.0, a cost-efficient co-work model obtained by further training the post-trained Qwen3.6-35B-A3B checkpoint. We construct execution-grounded data and environments, capture replayable long-horizon trajectories across multiple harnesses, and use staged post-training to develop and consolidate complementary execution capabilities. Across a broad suite of co-work benchmarks, Occamy-1.0 is consistently among the strongest comparably sized models and remains competitive with substantially larger frontier systems on several tasks. Under our stated evaluation and pricing protocol, its aggregate performance across four representative benchmarks places it at the low-cost knee of the observed cost--performance Pareto frontier. Supporting evaluations in tool calling, coding, and instruction following further show that this specialization preserves broad agentic capability. We release the model weights and a subset of the training data to support research on practical co-work agents and agentic post-training.

An engineered nanopore identifies saccharides, amino acids, peptides and ribonucleotides

Nature Biotechnology, Published online: 14 September 2026; doi:10.1038/s41587-026-03308-9

Modified nanopore simultaneously identifies diverse biomolecules and their modifications.

Advanced and underlying therapeutic strategies in transformed small cell lung cancer

Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

Advanced and underlying therapeutic strategies in transformed small cell lung cancer

Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9-13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3, MYC, SOX2, and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

SAM: State-Adaptive Memory for Long-Horizon Reasoning Agent

arXiv:2605.24468v1 Announce Type: new Abstract: Long-horizon agentic reasoning requires large language models to act over long interaction histories containing thoughts, tool calls, observations, and partial conclusions. The challenge is not merely that these histories grow long, but that information needed for the current decision may be scattered across distant steps and only become relevant later. Existing approaches address this difficulty by truncating the interaction history, compressing it into shorter surrogates, or retrieving selected parts of it for reuse, but they do not explicitly model how access to past interaction should adapt to the agent's evolving state. We instead cast long-horizon reasoning as a problem of state-adaptive memory. To this end, we propose State-Adaptive Memory~(SAM), a standalone framework that consolidates ongoing interaction into compact memory cues while preserving raw trajectory pages for intent-driven recall. These cues are not treated as replacements for history; rather, they serve as lightweight handles that allow the agent to reconstruct temporally distant information according to its current needs, without retraining the underlying backbone. We further optimize the memory module through expert-guided supervision and reinforcement learning, aligning it with trajectory-level utility. Across BrowseComp, BrowseComp-ZH, WideSearch, and HLE, SAM consistently outperforms strong baselines over diverse agent backbones. Our results suggest that explicit memory modeling provides a simple and effective foundation for long-horizon agentic reasoning.

AgentFugue: Agent Scaling for Long-Horizon Tasks through Collective Reasoning

arXiv:2605.24486v1 Announce Type: new Abstract: Recent progress on long-horizon agentic tasks has been driven largely by scaling up individual agents through stronger models, better tools, and more effective scaffolding. In contrast, much less is understood about scaling out: whether multiple peer agents, all targeting the same task, can become an additional source of capability without relying on explicit role specialization or workflow orchestration. We study this question and propose AgentFugue, a collective reasoning framework built around a shared reasoning hub. As peer agents explore the same task in parallel, the hub records concise notes on what each agent has established, attempted, or ruled out, and enables each agent to selectively access what other agents have discovered in a form useful for its current search. This design turns otherwise isolated trajectories into a connected ecology of reusable intermediate reasoning without requiring centralized planning. We instantiate the hub as a plug-in communication layer, trained with supervised fine-tuning and end-to-end reinforcement learning. Across the challenging long-horizon settings we study, AgentFugue improves over strong baselines. Our results suggest that collective reasoning can turn scaling out peer agent systems into a distinct source of capability gains, rather than merely a way of spending more compute.

Hera: Learning Long-Horizon Coordination for Device-Cloud Collaborative LLM Agents

arXiv:2605.24598v1 Announce Type: new Abstract: Large language model (LLM) agents excel at solving complex long-horizon tasks through autonomous interaction with environments. However, their real-world deployment faces a fundamental device--cloud dilemma: on-device models are efficient but often brittle, while cloud models are stronger but costly in computation. State-of-the-art LLM device--cloud routers usually make coarse task-level decisions, which cannot adapt to the changing difficulty of multi-step agent interactions. To address this issue, we present Hera, a step-level device--cloud LLM agent coordinator for long-horizon tasks achieving a strong performance--cost Pareto frontier. Hera adopts a novel two-stage training paradigm: (1) imitation learning for cold-start, followed by (2) reinforcement learning that jointly optimizes task success and cloud usage efficiency. The first stage casts step-level routing as a supervised classification problem: the device agent is replayed on cloud trajectories, with each state labeled by the agreement between device and cloud actions. In the second stage, we perform cost-aware reinforcement learning by grouping identical states across trajectories and updating Hera with labels favoring higher expected return and fewer future cloud calls. We evaluate Hera on ALFWorld, WebShop, and AppWorld, where it consistently outperforms prior methods, achieving 92.5% of the cloud-only success rate with cloud use in only 46.3% of steps.

Bridging the Semantic-Action Gap in Visual Token Pruning for Efficient VLA Inference

arXiv:2511.16449v5 Announce Type: replace-cross Abstract: Vision-Language-Action (VLA) models have shown great potential for embodied AI by integrating visual perception, language understanding, and action execution. In real-time deployment, these models must process continuous visual streams, incurring substantial computational overhead. Visual token pruning -- a mainstream technique for accelerating Vision-Language Models (VLMs) by retaining salient tokens while discarding redundant ones -- offers a natural candidate solution to this challenge. However, directly applying VLM-oriented pruning methods to VLA inference can cause severe degradation in manipulation performance. Our analysis attributes this degradation to a key mismatch: VLA inference exhibits distinct attention patterns between the vision-language prefill stage and the action-decode stage, so pruning based only on context-prefill semantic salience is biased toward semantic cues and may remove action-critical visual tokens. Motivated by this observation, we propose VLA-Pruner, an effective plug-and-play token pruning method grounded in the visual requirements of VLA inference, further exploiting the temporal continuity of robot manipulation. Specifically, VLA-Pruner estimates visual-token importance from both semantic prefilling and temporally smoothed action relevance, and then applies a Combine-then-Filter strategy to retain compact, non-redundant tokens under the compute budget. Experiments show that VLA-Pruner outperforms state-of-the-art approaches across multiple VLA architectures, achieving up to 1.99x speedup with comparable manipulation quality.

Ancient DNA reveals pervasive directional selection across West Eurasia

Nature, Published online: 15 April 2026; doi:10.1038/s41586-026-10358-1

Analysis of 15,836 ancient West Eurasian genomes reveals hundreds of instances of directional selection, showing that sustained changes in allele frequency were widespread, rather than being rare over this period as previously assumed.

StableTTA: Training-Free Test-Time Adaptation that Improves Model Accuracy on ImageNet1K to 96%

arXiv:2604.04552v1 Announce Type: cross Abstract: Ensemble methods are widely used to improve predictive performance, but their effectiveness often comes at the cost of increased memory usage and computational complexity. In this paper, we identify a conflict in aggregation strategies that negatively impacts prediction stability. We propose StableTTA, a training-free method to improve aggregation stability and efficiency. Empirical results on ImageNet-1K show gains of 10.93--32.82\% in top-1 accuracy, with 33 models achieving over 95\% accuracy and several surpassing 96\%. Notably, StableTTA allows lightweight architectures to outperform ViT by 11.75\% in top-1 accuracy while using less than 5\% of parameters and reducing computational cost by approximately 89.1\% (in GFLOPs), enabling high-accuracy inference on resource-constrained devices.

ContextDrag: Precise Drag-Based Image Editing via Context-Preserving Token Injection and Position-Aligned Attention

arXiv:2512.08477v2 Announce Type: replace-cross Abstract: Drag-based image editing enables intuitive visual manipulation through point-based drag operations. Existing methods mainly rely on diffusion inversion or pixel-space warping with inpainting. However, inversion inherently introduces approximation errors that degrade texture fidelity, whereas rigid pixel-space operations discard semantic context and produce unnatural deformations. To address these issues, we introduce ContextDrag, to our knowledge the first framework that brings drag-based manipulation into the in-context image editing paradigm. By leveraging the in-context capabilities of editing models (e.g., FLUX-Kontext), ContextDrag enables precise drag editing without inversion or fine-tuning. Specifically, we first propose Context-preserving Token Injection (CTI), which injects VAE-encoded reference features into attention layers at spatially aligned target positions, guided by latent-space correspondences estimated directly from user-specified control points. By operating on clean, directly encoded features rather than noisy inversion outputs, CTI preserves rich texture details and enables precise drag control. Second, we propose Position-Aligned Attention (PAA) to eliminate interference caused by spatial displacement of reference features. PAA re-encodes positional embeddings of displaced reference tokens to match their target locations, and masks overlapping regions between source and destination to prevent conflicting features from degrading visual consistency. Experiments on DragBench-SR and DragBench-DR demonstrate that ContextDrag achieves SOTA editing accuracy and overall quality, and comprehensive ablations validate the effectiveness of each proposed component. Code will be publicly available.
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  • Agentified Assessment of Logical Reasoning Agents Zhiyu Ni · Yifeng Xiao · Zheng Liang
    arXiv:2603.02788v4 Announce Type: replace Abstract: We present a framework for evaluating and benchmarking logical reasoning agents when assessment itself must be reproducible, auditable, and robust to execution failures. Building on agentified assessment, we use an assessor agent to issue tasks, enforce execution budgets, parse outputs, and record structured failure types, while the agent under test only needs to expose a standardized agent-to-agent interface. As a case study, we benchmark an
     

Agentified Assessment of Logical Reasoning Agents

arXiv:2603.02788v4 Announce Type: replace Abstract: We present a framework for evaluating and benchmarking logical reasoning agents when assessment itself must be reproducible, auditable, and robust to execution failures. Building on agentified assessment, we use an assessor agent to issue tasks, enforce execution budgets, parse outputs, and record structured failure types, while the agent under test only needs to expose a standardized agent-to-agent interface. As a case study, we benchmark an auto-formalization agent for first-order logic (FOL) reasoning on a solver-verified and repaired split of FOLIO. The agent translates natural language premises and conclusions into executable Z3Py programs and employs satisfiability modulo theories (SMT) solving to determine logical entailment. On the cleaned FOLIO validation set, the auto-formalization agent achieves 86.70% accuracy under the assessor protocol, outperforming a chain-of-thought baseline (73.89%).

Semantic Refinement with LLMs for Graph Representations

arXiv:2512.21106v2 Announce Type: replace-cross Abstract: Graph-structured data exhibit substantial heterogeneity in where their predictive signals originate: in some domains, node-level semantics dominate, while in others, structural patterns play a central role. This structure-semantics heterogeneity implies that no graph learning model with a fixed inductive bias can generalize optimally across diverse graph domains. However, most existing methods address this challenge from the model side by incrementally injecting new inductive biases, which remains fundamentally limited given the open-ended diversity of real-world graphs. In this work, we take a data-centric perspective and treat node semantics as a task-adaptive variable. We propose a Graph-Exemplar-guided Semantic Refinement (GES) framework for graph representation learning which -- unlike existing LLM-enhanced methods that generate node descriptions without graph context -- leverages structurally and semantically similar nodes from the graph itself to guide semantic refinement. Specifically, a GNN is first trained to produce predictive states, which along with structural and semantic similarity are used to retrieve in-graph exemplars that inform an LLM in refining node descriptions. We evaluate our approach on both text-rich and text-free graphs. Results show consistent improvements on semantics-rich and structure-dominated graphs, demonstrating the effectiveness of data-centric semantic refinement under structure-semantics heterogeneity.

iPoster: Content-Aware Layout Generation for Interactive Poster Design via Graph-Enhanced Diffusion Models

arXiv:2603.29469v1 Announce Type: cross Abstract: We present iPoster, an interactive layout generation framework that empowers users to guide content-aware poster layout design by specifying flexible constraints. iPoster enables users to specify partial intentions within the intention module, such as element categories, sizes, positions, or coarse initial drafts. Then, the generation module instantly generates refined, context-sensitive layouts that faithfully respect these constraints. iPoster employs a unified graph-enhanced diffusion architecture that supports various design tasks under user-specified constraints. These constraints are enforced through masking strategies that precisely preserve user input at every denoising step. A cross content-aware attention module aligns generated elements with salient regions of the canvas, ensuring visual coherence. Extensive experiments show that iPoster not only achieves state-of-the-art layout quality, but offers a responsive and controllable framework for poster layout design with constraints.

QuestA: Expanding Reasoning Capacity in LLMs via Question Augmentation

arXiv:2507.13266v4 Announce Type: replace-cross Abstract: Reinforcement learning (RL) has emerged as a central paradigm for training large language models (LLMs) in reasoning tasks. Yet recent studies question RL's ability to incentivize reasoning capacity beyond the base model. This raises a key challenge: how can RL be adapted to solve harder reasoning problems more effectively? To address this challenge, we propose a simple yet effective strategy via Question Augmentation: introduce partial solutions during training to reduce problem difficulty and provide more informative learning signals. Our method, QuestA, when applied during RL training on math reasoning tasks, not only improves pass@1 but also pass@k-particularly on problems where standard RL struggles to make progress. This enables continual improvement over strong open-source models such as DeepScaleR and OpenMath Nemotron, further enhancing their reasoning capabilities. We achieve new state-of-the-art results on math benchmarks using 1.5B-parameter models: 72.50% (+10.73%) on AIME24, 62.29% (+12.79%) on AIME25, and 41.67% (+10.11%) on HMMT25. Code, data and model are available at https://github.com/foreverlasting1202/QuestA.

Not All Tokens Are Created Equal: Query-Efficient Jailbreak Fuzzing for LLMs

arXiv:2603.23269v1 Announce Type: cross Abstract: Large Language Models(LLMs) are widely deployed, yet are vulnerable to jailbreak prompts that elicit policy-violating outputs. Although prior studies have uncovered these risks, they typically treat all tokens as equally important during prompt mutation, overlooking the varying contributions of individual tokens to triggering model refusals. Consequently, these attacks introduce substantial redundant searching under query-constrained scenarios, reducing attack efficiency and hindering comprehensive vulnerability assessment. In this work, we conduct a token-level analysis of refusal behavior and observe that token contributions are highly skewed rather than uniform. Moreover, we find strong cross-model consistency in refusal tendencies, enabling the use of a surrogate model to estimate token-level contributions to the target model's refusals. Motivated by these findings, we propose TriageFuzz, a token-aware jailbreak fuzzing framework that adapts the fuzz testing approach with a series of customized designs. TriageFuzz leverages a surrogate model to estimate the contribution of individual tokens to refusal behaviors, enabling the identification of sensitive regions within the prompt. Furthermore, it incorporates a refusal-guided evolutionary strategy that adaptively weights candidate prompts with a lightweight scorer to steer the evolution toward bypassing safety constraints. Extensive experiments on six open-source LLMs and three commercial APIs demonstrate that TriageFuzz achieves comparable attack success rates (ASR) with significantly reduced query costs. Notably, it attains a 90% ASR with over 70% fewer queries compared to baselines. Even under an extremely restrictive budget of 25 queries, TriageFuzz outperforms existing methods, improving ASR by 20-40%.

Graph Structure Learning with Privacy Guarantees for Open Graph Data

arXiv:2507.19116v3 Announce Type: replace-cross Abstract: Publishing open graph data while preserving individual privacy remains challenging when data publishers and data users are distinct entities. Although differential privacy (DP) provides rigorous guarantees, most existing approaches enforce privacy during model training rather than at the data publishing stage. This limits the applicability to open-data scenarios. We propose a privacy-preserving graph structure learning framework that integrates Gaussian Differential Privacy (GDP) directly into the data release process. Our mechanism injects structured Gaussian noise into raw data prior to publication and provides formal $\mu$-GDP guarantees, leading to tight $(\varepsilon, \delta)$-differential privacy bounds. Despite the distortion introduced by privatization, we prove that the original sparse inverse covariance structure can be recovered through an unbiased penalized likelihood formulation. We further extend the framework to discrete data using discrete Gaussian noise while preserving privacy guarantees. Extensive experiments on synthetic and real-world datasets demonstrate strong privacy-utility trade-offs, maintaining high graph recovery accuracy under rigorous privacy budgets. Our results establish a formal connection between differential privacy theory and privacy-preserving data publishing for graphical models.

Spatial Omics in Gastrointestinal Oncology: Recent Advances, Therapeutic Insights, and Clinical Translation

J Cancer. 2026 Jan 30;17(3):515-523. doi: 10.7150/jca.127381. eCollection 2026.

ABSTRACT

Gastrointestinal (GI) cancers remain a leading cause of cancer-related morbidity and mortality worldwide, largely due to their molecular heterogeneity, complex tumor microenvironment (TME), and variable treatment responses. In recent years, the emergence of spatially resolved omics technologies-encompassing spatial transcriptomics, proteomics, metabolomics, and epigenomics-has revolutionized the ability to interrogate tumor architecture with unprecedented resolution. These methods enable precise mapping of cellular and molecular interactions within intact tissue contexts, thereby uncovering spatially defined niches that influence tumor progression, immune evasion, and therapeutic resistance. In GI malignancies such as colorectal, gastric, and esophageal cancers, spatial omics have provided critical insights into cancer-stromal-immune crosstalk, identified predictive biomarkers for immunotherapy and targeted agents, and guided the development of novel therapeutic strategies. This review synthesizes the latest advances in spatial omics applied to GI oncology over the past five years, with an emphasis on their integration into early diagnosis, treatment stratification, and real-time monitoring of therapeutic efficacy. We also discuss current challenges, including standardization, data integration, and clinical validation, as well as future directions for incorporating spatial profiling into routine oncology practice. By bridging the gap between bench discoveries and bedside applications, spatial omics hold transformative potential for achieving truly personalized treatment in gastrointestinal cancers.

PMID:41869445 | PMC:PMC13003551 | DOI:10.7150/jca.127381

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